Alzheimer's disease (AD) is one of the most common and devastating degenerative diseases. Dementia doubles in frequency every five years after age 60, afflicting 1% of those aged 60-64 but rising to 30-40% percent of those 85 years and older. Examination at autopsy remains the only definitive method to diagnosis AD, leaving no reliable method during a patient's lifetime to know the onset of the disease, its progression or prognosis. Studies using Magnetic Resonance Imaging (MRI) have detected some areas of the brain that show gray matter and/or white matter structural changes in morphology and/or integrity, but none of these studies have been validated using corresponding histological analysis. Establishing a reliable imaging biomarker for the disease that is correlated with underlying pathology could provide a means by which physicians can provide a clear diagnosis and monitor micro and macrostructural changes in the brain that are associated with the different stages of dementia. In essence, a validated biomarker could be used as a tool to identify a fingerprint for the different stages of cognitive decline and help physicians find the appropriate treatment options for their afflicted patients. In this proposal, we will develop a histologically validated imaging biomarker for T1-weighted and Diffusion Tensor Imaging (DTI) of the hippocampus, entorhinal cortex of the parahippocampal gyrus, and cingulate gyrus from cadaveric control brain tissue and autopsy brain specimens. In general, this is an important innovation for determining the ground truth for imaging studies and for characterizing the true underlying cause of gray and white matter changes seen in AD. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) looms as the greatest threat to public health in the first half of the 21st Century, yet its definitive diagnosis remains limited autopsy examination. Using structural imaging and corresponding histological validation, this project will construct a validated imaging biomarker of the hippocampus, entorhinal cortex of the parahippocampal gyrus, and cingulate gyrus, all areas of the brain that are affected pathologically in the earliest stages of Alzheimer's disease (AD) dementia and throughout the course of the disease. We expect that the validated biomarker created through this project will assist with the diagnosis and prognosis of AD, thereby facilitating more treatment options for patients who are afflicted.